The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases.
Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphorylation in response to extracellular and other stimuli to cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H2O2), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factors (TNF-α)), and growth factors (e.g. granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.
Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, central nervous system disorders, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of α and β isoforms that are each encoded by distinct genes. Coghlan et al., Chemistry & Biology, 7,793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514(2000). GSK-3 has been implicated in various diseases including diabetes, CNS disorders such as manic depressive disorder, neurodegenerative diseases, such as Alzheimer's disease, and acute neuronal trauma (stroke and head trauma), cardiomyocete hypertrophy, and cancer. WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117. Inhibition of GSK-3 can also be useful in the treatment and prevention of disorders including Fragile X syndrome, autism, mental retardation, schizophrenia and Down's Syndrome. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor β-catenin, the translation initiation factor e1F2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBn. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development. (Meijer L. et al. (2004) “Pharmacological inhibitors or glycogen synthase kinase 3,” Trends Pharmacol. Sci. 25(9):471-480 and Wagman A. et al. (2004) “Discovery and Development of GSK-3 Inhibitors for the Treatment of Type 2 Diabetes,” Curr. Pharmaceutical Design, 10:1105-1137 provide recent reviews of GSK-3 inhibitors.)
In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake. Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299,123-128 (1994). However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type 11 diabetes, GSK-3 is overexpressed. WO 00/38675. Therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin.
GSK-3 activity has also been associated with Alzheimer's disease. Alzheimer's disease is among the most important health care problems in the world. The past decade has seen the adoption of the first class of medications, the cholinesterase inhibitors, effective in improving cognitive symptoms in Alzheimer's disease. These drugs provide symptomatic relief; effective disease-modifying therapy remains a major, elusive goal. Substantial efforts have been made to apply findings from laboratory research, as well as genetic and epidemiologic studies, to the identification of potential strategies for influencing Alzheimer's disease pathology. Alzheimer's disease is a progressive dementia which develops in late middle ages (45 to 65 years old) and its etiological changes are shrinkage of cerebral cortex due to a neuronal cell loss and degeneration of the neurons while, from the pathological view, many senile plaques and neurofibrillary tangles are noted in the brain. There is no pathologically substantial difference between the disease and senile dementia caused by the so-called natural aging which develops in the senile period of 65 years and older ages and, therefore, this disease is called senile dementia of Alzheimer type.
Alzheimer's disease is characterized by the well-known p-beta-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein, where Tau is phosphorylated on abnormal sites. GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells. Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport, 8, 3251-55 (1997). Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer's disease.
Another substrate of GSK-3 is β-catenin which is degraded after phosphorylation by GSK-3. Reduced levels of β-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death. Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997).
More than 2 million American adults, or about 1 percent of the population age 18 and older in any given year, have bipolar disorder (manic depressive disorder.) Current treatments include the so-called “mood stabilizers,” lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects.
Efforts to understand the mechanism of action of lithium, have demonstrated that specific inhibitors of the enzyme glycogen synthase kinase-3β (GSK-3β) mimic the therapeutic action of mood stabilizers and therefore have potential for improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. The pro-apoptotic properties of the GSK-3 enzyme also indicate a potential for such inhibitors as neuroprotective agents. Additionally, the neuroprotection function of such inhibitors may further contribute to their therapeutic efficacy of as mood disorder drugs. Certain inhibitors of GSK-3β have been shown to exert a neuroprotective action in vitro (Kozikowski, A. P.; Gaysina, I. N.; Petukhov, P. A.; Sridhar, J; King, L; Blond, S. Y.; Duka, T.; Rusnak, M.; Sidhu, A., ChemMedChem 2006, 1, (2), 256-266.) This work employed a cellular model of Parkinson's disease.
McBride, S. M. et al (2005) Pharmacological rescue of synaptic plasticity, courtship behavior and mushroom body defects in a Drosophila model of fragile X syndrome, Neuron 45:753-764 report that a Drosophila model of Fragile X can be treated with lithium or metabotropic glutamate receptor (MGluR) antagonists (see also: Raymond, F. L. and Tarpey P. (2006) The genetics of metal retardation. Human Molecular Genetics 15 (Review Issue No. 2) R110-R116). U.S. Pat. Nos. 6,916,821 and 6,890,931, report the use of Group I MGluR antagonists for the treatment and prevention of disorders, including Fragile X, autism, mental retardation, schizophrenia and Down's Syndrome. As well as for the treatment of epilepsy and anxiety in individuals having Fragile X syndrome, autism, mental retardation, schizophrenia and Down's Syndrome. As noted above, inhibitors of GSK-3β mimic the therapeutic action of lithium and as such are expected to be beneficial in the treatment of Fragile X syndrome and related disorders. Also GSK-3 is turned on by glutamate signaling indicating that antagonists of MGluR can affect GSK-3.
For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported recently as inhibitors of p38 kinase. WO 00/12497. The compounds are reported to be useful for treating conditions characterized by enhanced p38 activity and/or enhanced TGF-β activity. While p38 activity has been implicated in a wide variety of diseases, including diabetes, p38 kinase is not reported to be a constituent of an insulin-signaling pathway that regulates glycogen synthesis or glucose uptake. Therefore, unlike GSK-3, p38 inhibition would not be expected to enhance glycogen synthesis and/or glucose uptake.
Because of the biological importance of GSK-3, there has been significant interest in therapeutically effective GSK-3 inhibitors. The following references relate to small molecule inhibitors of GSK-3 and their applications.
U.S. Pat. No. 6,441,053 reports inhibitors of GSK-3 and methods for identifying and using such inhibitors for the treatment of GSK-3 related disorders which are indicated to include bipolar disorder, including mania, Alzheimer's disease, diabetes, and leucopenia. The reference further indicates that GSK-3 inhibitors are useful in the treatment of disorders of conditions that respond to administration of lithium, GSK-3 inhibitors are also indicated to be useful for reducing the motility of mammalian spermatozoa.
WO 00/38675 (Smithkline Beecham) reports certain bisindole maleimides, indolyl aryl maleimides and indolocarbazoles as inhibitors of GSK-3β. Such inhibitors are indicated to be useful in the treatment of diabetes, chronic neurodegenerative conditions, manic depression, mood disorders, such as schizophrenia, neurotraumatic diseases, such as acute stroke, hair loss and cancer.
WO 02/10158 (Hoffman-LaRoche) and U.S. Pat. No. 6,479,490 report 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives as inhibitors of GSK-3β. It is further reported that inhibition of GSK-3β activity reduces the level of CD4+ T-helper 2 cell (Th2). These cells produce cyctokines, promote IgE production and eosinophil differentiation. Th2-specific cytokines are important in the pathogenesis of allergies and asthma. This report indicates that inhibitors of GSK-3β are useful in the treatment of allergies and asthma.
WO 05/002552 (Astex Technology) reports certain compounds as inhibitors of cyclin dependent kinase, GSK-3 kinase and Aurora kinase. GSK-3 kinase is reported to be associated with embryonic development, protein synthesis, cell proliferation and differentiation, microtubule dynamics, cell motility, and cellular apoptosis. GSK-3 kinase is indicated to be implicated in diabetes, cancer, Alzheimer's disease, Huntington's disease, stroke, epilepsy, motor neuron diseases, and head trauma and as such inhibitors of GSK-3 kinase are useful in the treatment of such disease states. In particular, inhibitors of GSK-3 kinases are reported to be useful in treatment of cancer, particularly colorectal cancer, and in the treatment of disease or conditions characterized by neuronal apoptosis to limit and/or prevent neurodegeneration.
WO 05/111018 (Aventis) reports certain pyridazinone derivatives as inhibitors of GSK-3β. These inhibitors are reported to be useful in the treatment of neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration and Pick's disease), stroke, cranial and or spinal trauma, peripheral neuropathies, obesity, metabolic disease, type II diabetes, essential hypertension, atherosclerosis, cardiovascular diseases, polycystic ovary syndrome, syndrome X and immunodeficiency.
Published U.S. application U.S. 2006/0089369 (Chiron) reports certain pyrimidine or pyridine-based inhibitors of GSK-3 for treatment of disorders mediated by GSK-3 including diabetes, neurodegenerative disorders, including Alzheimer's disease, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, especially cerebral ischemia, traumatic brain injury, bipolar disorder, immunodeficiency and cancer. The reference states that agents that inhibit GSK-3 activity are useful in the treatment of disorders that are mediated by GSK-3 activity and that inhibition of GSK-3 mimics the activation of growth factor signaling pathways and consequently GSK3 inhibitors are useful in the treatment of diseases in which such pathways are insufficiently active.
Published U.S. application U.S. 2003/0176484 reports the use of inhibitors of GSK-3β in a mammal to promote bone formation, increase bone mineral density, reduce fracture rate, increase fracture healing rate, increase cancellous bone formation, increase new bone formation and to treat osteoporosis.
Published U.S. application U.S. 2006/0217368 reports GSK-3 inhibitors for nerve regeneration, and as agents for the promotion of neuropoiesis of neural stem cells. Drugs of the invention are reported to be useful as a therapeutic for neurological diseases such as Parkinson's disease, Alzheimer's disease, Down's disease, cerebrovascular disorder, cerebral stroke, spinal cord injury, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, anxiety disorder, schizophrenia, depression and manic depressive psychosis.
Published U.S. application 20050075276 reports the use of inhibitors of GSK-3α or β to augment CD28 dependent -T-cell responses. The invention is directed at least in part to a method of enhancing CD28 mediated and dependent T-cell responses against viral, bacterial, fungal or prion infections. Thus, inhibitors of GSK-3 are indicated to be useful in the treatment of viral, bacterial, fungal or prion infections.
U.S. Pat. Nos. 7,045,519, 7,037,918, 6,989,382, 6,977,262, 6,949,547, 6,800,632, 6,780,625, 6,608,063, 6,489,344, 6,479,490, and 6,417,185 relate to GSK-3 inhibitors. Published U.S. Patent applications U.S. 2005/0234120, 2004/0052822, 2004/0138273, and 2004/0210063 relate to GSK-3 inhibitors.
Inhibitors of GSK-3 have wide application as therapeutics and are in general important targets for pharmaceutical applications. A number of synthetic GSK-3 inhibitors have been reported, however, there remains a clear need for GSK-3 inhibitors that are potent, selective, safe, effective and which exhibit minimal undesired side-effects.
This invention relates at least in part to benzofuranyl derivatives of indolylmaleimides which are protein kinase inhibitors and particularly those which are GSK-3 inhibitors.
EP 1224932 relates to certain indolylmaleimides which are reported to be cell death inhibitors useful as pharmaceuticals or as a preservative for organs, tissues or cells. Compounds of formula:
are reported, where the variables are defined in the patent application. Among many other groups, R4 can be selected from an aryl group, other than 3-indolyl, which aryl group can be substituted. Compounds 18 and 19 in Table 1 of the reference have R4 that is an unsubstituted benzofuranyl, with R2 that is methyl and R1 that is H (18) or methyl (19). No test data are listed in Table 2 of the reference for either of compounds 18 or 19. There is nothing in the reference that indicates that either of these compounds is a protein kinase inhibitor and nothing that indicates that either of these compounds is an inhibitor of GSK-3.
Engler T. A., et al “The development of potent and selective bisarylmaleimide GSK3 inhibitors,” Bioorg. Med. Chem. Lett. (2005) Jan. 15:899-903 reports certain GSK3 inhibitors of formula:
where Ar was certain bicyclic heteroaromatic groups. Ar was reported to include:
among a number of additional Ar groups, where a is a benzofuran-7-yl group, b is a benzofuran-4-yl group and c is a benzofuran-3-yl group. Certain compounds including compounds in which Ar is a or b are reported to be potent and selective GSK3 inhibitors. Data for selectivity of inhibition of GSK-3 compared to inhibition of CDK2, CDK4 and PKCβII kinases is reported. Data is reported for a single compound where Ar is c and where R is H. This compound is reported to have GSK3 IC50 of 64 nM with ratio of IC50 of PKCβII/GSK3 of 37.
U.S. Pat. No. 5,721,245 (Davis) reports compounds of formula:
where among others X and Y are O, R1 and R2 taken together are a group of the formula —(CH2)n— or R1 and R7 taken together are a group of the formula —(CH2)n—, Z is N or CH, n is an integer from 1-5, m is an integer from 0 to 5 and R3 is an aryl or aromatic heterocyclic group. Aromatic heterocyclic is defined as “a 5-membered or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring” which can be substituted or unsubstituted. Exemplary heterocyclic groups are reported to be 2-thienyl, 3-thienyl, 3-benzothienyl, 3-benzofuranyl, 2-pyrrolyl, 3-indolyl and the like. Compounds are reported to be useful in the control or prevention of inflammatory, immunological, oncological, bronchopulmonary and cardiovascular disorders or in the treatment of asthma or AIDS. The compounds are further reported to be protein kinase inhibitors and as such inhibitors of cellular processes. The patent refers in particular to inhibition of protein kinase C.
WO 03/076398 and corresponding US 20050288321 report GSK-3 kinase inhibitors having the structure:
where Ar is benzofur-7-yl optionally substituted in the phenyl ring with R8 and R9, 1-(R7)-indo1-4-yl, benzofur-4-yl, quinolin-5-yl, quinolin-7-yl, isoquinolin-5-yl, isoquinolin-3-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl, furo[3,2-c]pyridin-7-yl, benzo[1,3]dioxo1-4-yl, 2,2-difluorobenzo[1,3]dioxo1-4-yl, or 2,3-dihydrobenzofur-7-yl optionally substituted in the phenyl ring with R8 and R9 and in the dihydrofuryl ring with C1-C4 alkyl and R8 is —NHCO2(C1-C4 alkyl), —NHSO2(C1-C4 alkyl), halo, amino, —O—(CH2)m-G, —NHC(O)(C1-C4 alkyl), C1-C4 alkoxy, hydroxyl, —O—R10, C1-C4 alkyl, C1-C4 alkylthio, or —(CH2)m-G and R9is halo, where G is hydroxyl, NR11R12 or piperidin-4-yl, R11 and R12 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, cyclopropylmethyl, benzyl, or, taken together with the nitrogen to which they are attached form a piperidine, 4-hydroxypiperidine, 4-(C1-C4 alkyl)piperidine, N—(R13)-piperazine, or morpholine ring where R13 is hydrogen, C(O)—(C1-C4 alkyl), or C1-C4 alkyl.
U.S. Pat. No. 5,057,614 (Davis) see also U.S. RE 36736 reports compounds of formula:
where R2 is hydrogen among other groups, and R1 is hydrogen, alkyl, aryl, araalkyl, hydroxyalkyl, and haloalkyl among other groups. These compounds are said to be inhibitors of protein kinase useful in the treatment of illnesses including inflammatory, immunological, bronchopulmonary and cardiovascular disorders where among others X and Y are O and R3 is a carbocyclic or heterocyclic aromatic group. The R3 heterocyclic aromatic group is reported to be a 5- or 6-membered heterocyclic aromatic group which can optionally carry a fused benzene ring and which can be unsubstituted or substituted, for example, with one or more, preferably one to three, substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, mono- or dialkylamino, alkylthio, alkylsulphinyl and alkylsulphonyl. Examples of R3 heterocyclic aromatic groups given in the patent are 2- or 3-thienyl, 3-benzothienyl, 1-methyl-2-pyrrolyl, 1-benzimidazolyl, 3-indolyl, 1- or 2-methyl-3-indolyl, 1-methoxymethyl-3-indolyl, 1-(1-methoxyethyl)-3-indolyl, 1-(2-hydroxypropyl)-3-indolyl, 1-(4-hydroxybutyl)-3-indolyl, 1-[I-(2-hydroxyethylthio)-ethyl]-3-indolyl, 1-[1-(2-mercaptoethylthio)ethyl]-3-indolyl, 1-(I-phenylthioethyl)-3-indolyl, I-[1-(carboxymethylthio)ethyl]-3-indolyl and 1-benzyl-3-indolyl.